Use of tivozanib to treat subjects with refractory cancer

ABSTRACT

Disclosed is a method of treating cancer, e.g., refractory cancer, with tivozanib. The methods disclosed include, for example, administering tivozanib as a second or third-line therapy to subjects suffering from refractory advanced renal cell carcinoma where traditional therapies as well as more recent targeted and immune-oncology therapies have not adequately treated the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalPatent Application No. 62/756,033 filed Nov. 5, 2018, the contents ofwhich are incorporated by reference herein in their entirety.

FIELD OF THE INVENTION

The field of the invention is medicine, oncology, tyrosine kinaseinhibitors, VEGF receptor inhibitors, and pharmaceuticals.

BACKGROUND

Tivozanib (previously known as AV-951 and KRN951) is a potent andselective small-molecule inhibitor of vascular endothelial growth factor(VEGF) receptor tyrosine kinase inhibitor (VEGF TKI) that hasdemonstrated significant anti-tumor effects in pre-clinical experiments.(Nakamura et al., 2006, CANCER RES. 66:9134-9142).

Tivozanib inhibits phosphorylation of VEGF receptors (VEGFR)-1, -2 and-3 at picomolar concentrations (IC50 of 0.21, 0.16 and 0.24 nMrespectively), and inhibits c-Kit and platelet derived growth factorreceptor (PDGFR) at 10-times higher concentrations (IC50 of 1.63 and1.72 nM respectively).

Based on its biochemical profile, tivozanib appears to be one of themost potent and selective VEGF tyrosine kinase inhibitors in clinicaldevelopment. Other agents used for treatment of renal cell carcinoma(RCC) such as sunitinib and sorafenib inhibit multiple tyrosine kinasesin addition to the VEGF receptor tyrosine kinase, leading to off-targettoxicities such as fatigue, hand-foot syndrome, stomatitis, andneutropenia. However, the adverse event (AE) profile of tivozanibdemonstrates that it is a selective VEGF tyrosine kinase inhibitor, withminimal off-target toxicities. In a prior phase III clinical trialcomparing tivozanib and sorafenib, tivozanib had fewer treatmentinterruptions and dose reductions due to AEs. (Motzer et al. (2013), J.Clinical Oncology, 31:3791-3799).

Approximately 208,500 new cases of kidney cancer are diagnosed in theworld each year, of which 40,000 new cases are diagnosed in NorthAmerica and 63,300 new cases in the European Union (EU). Renal cellcarcinoma accounts for 80%-85% of all malignant kidney tumors. AdvancedRCC is highly resistant to chemotherapy, and interleukin-2 andinterferon-α have low levels of anti-tumor activity. Recently, drugsthat block the VEGF pathway such as sunitinib, sorafenib, bevacizumab,pazopanib, and axitinib have demonstrated significant anti-tumoractivity in Phase 3 trials. As a result, these drugs have become thestandard of care for the treatment of subjects with advanced RCC.

The various forms of VEGF bind to 3 tyrosine kinase receptors: thevascular endothelial growth factor receptors, VEGFR-1, VEGFR-2, andVEGFR-3 retrospectively. This binding results in phosphorylation of thereceptors catalyzed by the protein kinase, and the promotion of a signaltransduction cascade. Deregulation of VEGF expression contributes to theprogression and spread of solid tumors by promoting tumor angiogenesis(Neufeld et al., (1999), FASEB J., 13:9-22). Tivozanib inhibitsVEGFR-associated tyrosine kinase activity and, as a result, may offer apotential therapy for subjects with cancer by controlling tumor growth.

Further, in subjects for whom first and second line therapies againstrenal cell carcinoma fail, such as sunitinib, sorafenib, bevacizumab,pazopanib, axitinib or checkpoint inhibitors (e.g., PD-1 and PD-L1inhibitors), there is still a need for additional therapies for treatingsuch subjects.

SUMMARY OF THE INVENTION

The present invention provides improved methods of treating subjectswith advanced and refractory cancers, such as renal cell carcinoma. Themethods comprise administering to subject in need of such treatment aneffective amount or an effective treatment regimen of tivozanib.

In one aspect, the invention provides a method of treating a subjectsuffering from advanced or refractory cancer wherein the subject haspreviously been treated with at least one anti-cancer therapy. Themethod comprises administering to the subject an effective amount or aneffective treatment regimen of tivozanib. In one embodiment, the subjectsuffers from refractory cancer.

In another aspect, the invention provides a method of treating a subjectsuffering from advanced or refractory renal cell carcinoma wherein thesubject has previously been treated with at least one anti-cancertherapy. The method comprises administering to the subject an effectiveamount or an effective treatment regimen of tivozanib. In oneembodiment, the subject suffers from refractory renal cell carcinoma.

In certain embodiments of any of the foregoing methods, the methodcomprises administering to the subject a pharmaceutical compositioncomprising 1.5 mg tivozanib for 21 days followed by 7 days withoutadministration of tivozanib, wherein administering the tivozanib for 21days followed by 7 days without administration constitutes a treatmentcycle.

In another aspect, the invention provides a method of treating a subjectsuffering from refractory cancer wherein the subject has previously beentreated with at least one anti-cancer therapy. The method comprisesadministering to the subject a pharmaceutical composition comprising 1.5mg tivozanib for 21 days followed by 7 days without administration oftivozanib, wherein administering the tivozanib for 21 days followed by 7days without administration constitutes a treatment cycle.

In another aspect, the invention provides a method of treating a subjectsuffering from refractory renal cell carcinoma wherein the subject haspreviously been treated with at least one anti-cancer therapy. Themethod comprises administering to the subject a pharmaceuticalcomposition comprising 1.5 mg tivozanib for 21 days followed by 7 dayswithout administration of tivozanib, wherein administering the tivozanibfor 21 days followed by 7 days without administration constitutes atreatment cycle.

In certain embodiments of any of the foregoing methods: (a) the subjecthas previously been treated with at least one checkpoint inhibitor; (b)the subject has previously been treated with at least one vascularendothelial growth factor receptor tyrosine kinase inhibitor (VEGFRTKI); (c) the subject has previously been treated with a vascularendothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI)and a checkpoint inhibitor; or (d) the subject has previously beentreated with two vascular endothelial growth factor receptor tyrosinekinase inhibitors (VEGFR TKI). For example, in one embodiment, thesubject has previously been treated with at least one checkpointinhibitor. In another embodiment, the subject has previously beentreated with at least one vascular endothelial growth factor receptortyrosine kinase inhibitor (VEGFR TKI). In yet another embodiment, thesubject has previously been treated with a vascular endothelial growthfactor receptor tyrosine kinase inhibitor (VEGFR TKI) and a checkpointinhibitor. In a still further embodiment, the subject has previouslybeen treated with two vascular endothelial growth factor receptortyrosine kinase inhibitors (VEGFR TKI).

In certain embodiments of any of the foregoing methods, the subject hasnot responded to or has stopped responding to previous treatment with:(a) at least one checkpoint inhibitor; (b) at least one vascularendothelial growth factor receptor tyrosine kinase inhibitor (VEGFRTKI); (c) a vascular endothelial growth factor receptor tyrosine kinaseinhibitor (VEGFR TKI) and a checkpoint inhibitor; or (d) two vascularendothelial growth factor receptor tyrosine kinase inhibitors (VEGFRTKI). For example, in one embodiment, the subject has not responded toor has stopped responding to previous treatment with at least onecheckpoint inhibitor. In another embodiment, the subject has notresponded or has stopped responding to previous treatment with at leastone vascular endothelial growth factor receptor tyrosine kinaseinhibitor (VEGFR TKI). In yet another embodiment, the subject has notresponded to or has stopped responding to previous treatment with avascular endothelial growth factor receptor tyrosine kinase inhibitor(VEGFR TKI) and a checkpoint inhibitor. In a still further embodiment,the subject has not responded to or has stopped responding to previoustreatment with two vascular endothelial growth factor receptor tyrosinekinase inhibitors (VEGFR TKI).

In another aspect, the invention provides a method of treating a subjectsuffering from renal cell carcinoma (e.g., advanced and/or refractoryrenal cell carcinoma). The method comprises administering to the subjectan effective amount or an effective treatment regimen of tivozanib incombination with a checkpoint inhibitor. In certain embodiments,tivozanib is administered concurrent with the checkpoint inhibitor. Incertain embodiments, tivozanib is administered subsequent to thecheckpoint inhibitor. In certain embodiments, tivozanib and thecheckpoint inhibitor are a first line therapy. In certain embodiments,the checkpoint inhibitor is a first line therapy and tivozanib is asecond line therapy. In certain embodiments, the checkpoint inhibitor isa second line therapy and tivozanib is a third line therapy. In certainembodiments, the checkpoint inhibitor is a first line therapy andtivozanib is a third line therapy.

In certain embodiments of any of the foregoing methods, the methodcomprises administering to the subject a pharmaceutical compositioncomprising 1.5 mg tivozanib for 21 days followed by 7 days withoutadministration of tivozanib, wherein administering the tivozanib for 21days followed by 7 days without administration constitutes a treatmentcycle.

In certain embodiments of any of the foregoing methods, the subject isidentified as having an International Metastatic-RCC Database Consortium(IMDC) risk score of favorable or intermediate prior to treating thesubject. In certain embodiments, the IMDC risk category is favorable. Incertain embodiments, the IMDC risk category is intermediate.

In certain embodiments of any of the foregoing methods, the subject waspreviously treated with at least two anti-cancer therapies (e.g., afirst line anti-cancer therapy and a second line anti-cancer therapy).In one embodiment, the first line and second line anti-cancer therapiesare both VEGFR TKI therapies. In another embodiment, the first andsecond line anti-cancer therapies are a VEGFR TKI and a checkpointinhibitor, in either order, for example, the first line anti-cancertherapy is a VEGFR TKI and the second line therapy is a checkpointinhibitor. In another embodiment, the first line and second lineanti-cancer therapies are a VEGFR TKI and a systemic anti-cancer agent,in either order. In another embodiment, the first line and second lineanti-cancer therapies are a checkpoint inhibitor and a systemicanti-cancer agent, in either order.

In another aspect, the invention provides a method of treating a subjectsuffering from refractory cancer wherein the subject has previously beentreated with a vascular endothelial growth factor receptor tyrosinekinase inhibitor (VEGFR TKI) and a checkpoint inhibitor. The methodcomprises administering to the subject a pharmaceutical compositioncomprising 1.5 mg tivozanib for 21 days followed by 7 days withoutadministration of tivozanib, wherein administering the tivozanib for 21days followed by 7 days without administration constitutes a treatmentcycle. In one embodiment, the refractory cancer is refractory renal cellcarcinoma.

In another aspect, the invention provides a method of treating a subjectsuffering from refractory cancer wherein the subject has been previouslytreated with two vascular endothelial growth factor receptor tyrosinekinase inhibitors (VEGFR TKI). The method comprises administering to thesubject a pharmaceutical composition comprising 1.5 mg tivozanib for 21days followed by 7 days without administration of tivozanib, whereinadministering the tivozanib for 21 days followed by 7 days withoutadministration constitutes a treatment cycle. In one embodiment, therefractory cancer is refractory renal cell carcinoma.

In another aspect embodiment, the invention provides a method oftreating a subject suffering from refractory cancer wherein the subjectis identified as having an International Metastatic-RCC DatabaseConsortium (IMDC) risk score of favorable or intermediate prior totreating the subject. The method comprises administering to the subjecta pharmaceutical composition comprising 1.5 mg tivozanib for 21 daysfollowed by 7 days without administration of tivozanib, whereinadministering the tivozanib for 21 days followed by 7 days withoutadministration constitutes a treatment cycle.

In certain embodiments of any of the foregoing methods, the refractorycancer is refractory renal cell carcinoma. In certain embodiments,tivozanib is administered in the form of tivozanib hydrochloridemonohydrate. In certain embodiments, the subject undergoes one or moretreatment cycles with tivozanib.

In certain embodiments of any of the foregoing methods, the VEGFR TKI issorafenib, sunitinib, pazopanib, crizotinib, vandetinib, axitinib,cabozantinib, regorafenib, axinitib, or nintedanib. In certainembodiments, the checkpoint inhibitor is an anti-PDL1 or anti-PD1inhibitor (e.g., nivolumab, pembrolizumab, cemiplimab, spartalizumab,camrelizumab, sintilimab, tislelizumab, toripalimab, prolgolimab,cetrelimab, pidilizumab, BMS-936559, MDX-1105, atezolizumab, durvalumab,or avelumab) or an anti-CTLA-4 inhibitor (e.g., ipilimumab). In certainembodiments, the systemic anti-cancer agent is everolimus ortemsirolimus.

In certain embodiments of any of the foregoing methods, the subjectundergoes one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, or more than twelve treatment cycles. In certainembodiments, the subject exhibits a complete or partial response totivozanib after one treatment cycle, after two treatment cycles, orafter three, four, five, six, seven, eight, nine, ten, eleven, or twelvetreatment cycles. In certain embodiments, the subject is administeredtivozanib for one, two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, or more than twelve months.

In certain embodiments of any of the foregoing methods, the dose oftivozanib is reduced when a subject experiences a ≥Grade 3 drug-relatedadverse event, moderate hepatic impairment (Child-Pugh class B), orsevere hepatic impairment (Child-Pugh class C). In certain embodiments,the dose may be reduced to 1.0 mg daily, 1.5 mg every other day, or 1.0mg every other day.

These and other aspects and features of the invention are described inthe following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be more completely understood with reference to thefollowing drawings.

FIG. 1 illustrates the Kaplan-Meier Analysis of Independent RadiologicalReview (IRR) progression-free survival (PFS) in months stratified byIMDC (International Metastatic Renal Cell Carcinoma Database Consortium)risk and prior therapy for subjects receiving tivozanib, compared to PFSfor subjects receiving sorafenib.

FIG. 2 illustrates the Kaplan-Meier Analysis of overall survival (OS) inmonths for subjects receiving tivozanib, compared to OS for subjectsreceiving sorafenib.

FIG. 3 is a tabulation of Best Overall Response (BOR) and ObjectiveResponse Rate (ORR) for subjects receiving tivozanib, compared to BORand ORR for subjects receiving sorafenib. Numbers in parentheses showthe percentage of patients falling within each category.

FIG. 4 is a tabulation of unstratified Kaplan-Meier Analysis of IRRProgression Free Survival for subjects receiving tivozanib, compared toPFS for subjects receiving sorafenib. Numbers in parentheses show thepercentage of patients falling within each category.

FIG. 5 is a tabulation of the Kaplan-Meier Analysis of IRR ProgressionFree Survival for a subset of subjects who received Prior Check PointInhibitor treatment comparing PFS for subjects receiving tivozanib, toPFS for subjects receiving sorafenib. Numbers in parentheses show thepercentage of patients falling within each category.

FIG. 6 is a tabulation of the Kaplan-Meier Analysis of IRR ProgressionFree Survival stratified by IMDC Risk Category and Prior Therapy (AsRandomized) in the Intent to Treat Population. Numbers in parenthesesshow the percentage of patients falling within each category.

FIG. 7 is a tabulation of the Kaplan-Meier Analysis of Overall Survival(OS) of subjects receiving tivozanib compared to subjects receivingsorafenib. Numbers in parentheses show the percentage of patientsfalling within each category.

FIG. 8 is a tabulation of the Kaplan-Meier Analysis of Overall Survival(OS) for a subset of subjects who received Prior Check Point Inhibitortreatment comparing OS for subjects receiving tivozanib, to OS forsubjects receiving sorafenib. Numbers in parentheses show the percentageof patients falling within each category.

FIG. 9 is a Forest plot of Hazard Ratio with 95% Confidence Interval forProgression Free Survival of various patient subgroups.

FIG. 10 is a tabulation of the subgroup analysis of Progression FreeSurvival (PFS) using Cox Model in the intent to treat (ITT) population.

FIG. 11 is a Forest plot of Hazard Ratio with 95% Confidence Intervalfor Overall Survival (OS) of various patient subgroups.

FIG. 12 is a tabulation of the subgroup of analysis of Overall Survival(OS) using Cox Model in the intent to treat (ITT) population.

FIG. 13 is a tabulation of the Best Overall Response Rate based on priortherapies.

FIG. 14 is a tabulation of the Duration of Response in the ITTpopulation of subjects exhibiting objective response.

DETAILED DESCRIPTION OF THE INVENTION

The invention generally relates to methods of treating cancer, forexample, advanced or refractory cancer, with tivozanib. In one aspect,the invention relates to methods of (i) reducing tumor growth and/or(ii) increasing survival rates, such as progression free survival rates(PFS), of subjects suffering from an advanced or refractory cancer,e.g., renal cell carcinoma (RCC), e.g., advanced or refractory renalcell carcinoma. In certain embodiments, the disclosed methods are basedon using tivozanib, a VEGF receptor tyrosine kinase inhibitor (VEGFRTKI), as a third line therapy in subjects suffering from RCC, e.g.,advanced or refractory renal cell carcinoma, where first and second linetreatments have failed to reduce tumor growth or increase survivalrates, or where first and second line treatments have lost efficacyafter initially successful treatment.

As shown in the examples that follow, tivozanib has a statisticallysignificant effect on improving PFS in subjects suffering from RCC ascompared to PFS in subjects treated with sorafenib, another VEGFR TKI.Without wishing to be bound by theory, it is believed that tivozanib'sability to suppress T-regulatory cells may explain, in part, tivozanib'ssuperior performance as compared to sorafenib with respect to PFS andmay also explain, in part, the relatively reduced occurrence and/orseverity of adverse events (AEs) during treatment. For example,tivozanib demonstrated superior properties relative to sorafenib whenused to treat subjects that had been previously subjected to treatmentwith a checkpoint inhibitor, such as a PD-1 or PD-L1 checkpointinhibitor or a VEGFR TKI.

I. Definitions

For convenience, certain terms in the specification, examples, andappended claims are collected in this section.

As used herein, “pharmaceutically acceptable” or “pharmacologicallyacceptable” mean molecular entities and compositions that do not producean adverse, allergic or other untoward reaction when administered to ananimal, or to a human, as appropriate. The term, “pharmaceuticallyacceptable carrier” includes any and all solvents, dispersion media,coatings, antibacterial and antifungal agents, isotonic and absorptiondelaying agents and the like. The use of such media and agents forpharmaceutical active substances is well known in the art. Exceptinsofar as any conventional media or agent is incompatible with theactive ingredient, its use in the therapeutic compositions iscontemplated. Supplementary active ingredients can also be incorporatedinto the compositions.

As used herein, “tivozanib” meansN-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-N′-(5-methyl-3-isoxazolyl)ureaand having the following chemical structure:

including pharmaceutically acceptable salts, solvates, solvates of apharmaceutically acceptable salt, esters, or polymorphs thereof. See,for example, U.S. Pat. Nos. 6,821,987, 7,166,722 and 7,211,587, each ofwhich are incorporated herein by reference in their entirety. In certainembodiments, tivozanib isN-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-N′-(5-methyl-3-isoxazolyl)ureaor hydrates of a hydrochloride salt. In certain embodiments, tivozanibisN-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]-phenyl}-N′-(5-methyl-3-isoxazolyl)ureamonohydrochloric acid salt monohydrate. In certain embodiments,tivozanib is tivozanib hydrochloride having the chemical name1-{2-chloro-4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-3-(5-methylisoxazol-3-yl)ureahydrochloride hydrate having the chemical structure

the molecular formula C₂₂H₁₉ClN₄O₅.HCl.H₂O, and a molecular weight of509.34.

As used herein, the term “Progression-Free Survival (PFS)” is defined asthe time from randomization to first documentation of objective tumorprogression (progressive disease “PD”, radiological) according to RECIST(Version 1.1; see, e.g., Eisenhauer et al. (2009), Eur. J. Cancer,25:228-247) or death due to any reason, whichever comes first. PFS datais censored on the day following the date of last tumor assessmentdocumenting absence of PD for subjects who do not have objective tumorprogression and are still on study at the time of the analysis, aregiven anti-tumor treatment other than the study treatment, or are movedfrom treatment follow-up prior to documentation of objective tumorprogression. Subjects having no tumor assessments after randomizationwho are not known to have died have PFS censored on the date ofrandomization.

As used herein, the term “Overall survival (OS)” is defined as the timefrom the date of randomization to date of death due to any cause. In theabsence of confirmation of death, survival time is censored at the lastdate the subject is known to be alive. Subjects lacking data beyondrandomization have their survival times censored on the date ofrandomization.

As used herein, the term “Objective response rate (ORR)” is defined asthe proportion of subjects with confirmed complete response (CR) orconfirmed partial response (PR) according to RECIST (Version 1.1),relative to the total population of randomized subjects. Confirmedresponses are those that persist on repeat imaging study at least 4weeks after the initial documentation of response.

As used herein, the term “Duration of response (DoR)” is defined as thetime from the first documentation of objective tumor response to thefirst documentation of objective tumor progression or to death due toany cause. DoR data is censored on the day following the date of thelast tumor assessment documenting absence of PD for subjects who do nothave tumor progression and are still on the study at the time of ananalysis, are given antitumor treatment other than the study treatment,are removed from the study follow-up prior to documentation of objectivetumor progression, died of non-cancer related cause, including death dueto unknown cause in the absence of documented disease progression. DoRis only calculated for the subgroup of subjects with an objective tumorresponse (PR or CR).

As used herein, the terms “response” or “responding” in the context of asubject's response to tivozanib refer to the RECIST (Response EvaluationCriteria in Solid Tumors, version 1.1, 2009) criteria for evaluatingresponse of target lesions to a cancer therapy. According to the RECISTcriteria, subjects who respond are categorized as either “completeresponders” (disappearance of all target lesions) or “partialresponders” (at least a 30% decrease in the sum of the longest diameterof target lesions, taking a reference the baseline sum longestdiameter); non-responders are placed into one of two categories: stabledisease (neither sufficient shrinkage to qualify for partial responsenor sufficient increase to qualify for progressive disease, taking asreference the smallest sum longest diameter since start of treatment) orprogressive disease (at least a 20% increase in the sum of the longestdiameter of target lesions, taking as reference the smallest sum longestdiameter recorded since treatment started or the appearance of one ormore new lesions). The RECIST criteria are discussed in detail in, e.g.,Therasse et al., J. Natl. Cancer Inst., 2000: 92:205-216 (RECIST 1.0),and Eisenhauer et al., Eur. J. Cancer, 2009: 25:228-247 (RECIST 1.1).Accordingly, as described herein, responding to therapy refers tosubjects falling within the RECIST categories of complete or partialresponder, whereas not responding refers to subjects falling within theRECIST categories of stable disease or progressive disease.

As used herein, the terms “treating” or “treat” or “treatment” in thecontext of cancer refer to applying techniques, actions or therapies toa subject that (a) slow tumor growth, (b) halt tumor growth, (c) promotetumor regression or disappearance, (d) ameliorate a symptom of thecancer, (e) cure the cancer, or (f) prolong survival of the subject, orapplying techniques, actions or therapies to a subject in an attempt toachieve any of (a)-(f) regardless of whether the individual actuallyresponds to the technique, action or therapy.

As used herein, the term “clinical benefit” refers to a subjectexperiencing any of (a) slowing of tumor growth, (b) halting of tumorgrowth, (c) tumor regression or disappearance, (d) amelioration of asymptom of the cancer, (e) curing the cancer, or (f) prolonging survivalof the subject.

As used herein, “advanced” with respect to a cancer or tumor (e.g.,renal cell carcinoma) refers to cancer or tumor that has reached Stage 3or Stage 4. In certain embodiments, “advanced” means that the cancer ortumor has metastasized, or otherwise cannot be adequately treated withlocal therapy, such as surgical intervention or radiation therapy,alone, and therefore requires a systemic therapy. In certainembodiments, “advanced” means that the cancer or tumor has recurredafter having responded to treatment with a local or systemic therapy.

As used herein, “refractory” refers to a cancer or tumor in a subjectthat fails to respond to a mode of treatment, e.g., the subject fails toattain a clinical benefit, or experiences disease progression. Aparticular type of cancer or tumor may be refractory to an initialtreatment, or may initially respond, but may at a later time fail tofurther respond, develop resistance or otherwise become “refractory” tosuch treatment. In certain embodiments, “refractory” refers to a canceror tumor, such as a renal cell carcinoma, that has been treated with atleast one systemic treatment, and has not responded to such treatment,or has continued to progress after such treatment. In anotherembodiment, “refractory” refers to a cancer or tumor, such as renal cellcarcinoma, that has been treated with at least two systemic treatments,and has not responded to such treatments, or has continued to progressafter such treatments.

As used herein, the terms “subject” and “patient” are usedinterchangeably and refer to an organism to be treated by the methodsand compositions of the present invention. Such organisms are preferablya mammal (e.g., human, mouse, rat, guinea pig, dog, cat, horse, cow,pig, or non-human primate, such as a monkey, chimpanzee, baboon, andrhesus), and more preferably, a human.

As used herein, the term “drug related adverse event,” “adverse event”or “AE” refers to adverse events as defined and classified in theNational Cancer Institute—Common Terminology Criteria for Adverse Events(CTCAE) version 4.03 dated Jun. 14, 2010, and any reference to “Grade”of adverse event refers to the grading system as outlined therein.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “International Metastatic-RCC DatabaseConsortium (IMDC) risk score refers to a risk score for RCC determinedbased upon the following criteria:

IMDC CLASSIFICATION CRITERION NO YES <1 year from time of diagnosis tosystemic therapy 0 +1 Kamofsky Performance Status <80% 0 +1 Hemoglobin <lower limit of normal [Usually ~120 g/L or 0 +1 12 g/dL] Correctedcalcium > upper limit of normal [Usually ~8.5- 0 +1 10.2 mg/dL]Neutrophils > upper limit of normal [Usually ~2.0-7.0 × 0 +1 10⁹/L]Platelets > upper limit of normal [Usually ~150,000- 0 +1 400,000cells/μL]For example, a “favorable” IMDC score is 0, whereas an “intermediate”score is 1-2, and a “poor” score is 3 based on these criteria, as shownbelow.

RISK CATEGORY IMDC No. MEDIAN SURVIVAL* Favorable 0 35.3-43.2 mosIntermediate 1-2 16.6-22.5 mos Poor  3+  5.4-7.8 mos *Median Survivalranges based on the following references:https://www.mdcalc.com/imdc-intemational-metastatic-rcc-database-consortium-risk-score-rccKo et al. (2015) The Lancet 16: 293-300.

As used herein, the term “effective amount” refers to the amount of anactive agent (e.g., tivozanib) sufficient to effect beneficial ordesired results, such as, for example, to effect a clinical benefit in asubject. An effective amount can be administered in one or moreadministrations, applications or dosages and is not intended to belimited to a particular formulation or administration route.

As used herein, the term “effective treatment regimen of tivozanib”refers to a treatment regimen of tivozanib sufficient to effectbeneficial or desired results, such as to effect a clinical benefit in asubject. An effective treatment regimen of tivozanib can be administeredin one or more administrations, applications or dosages and is notintended to be limited to a particular formulation or administrationroute. An exemplary effective treatment regimen of tivozanib is aregimen that is effective to elicit a complete or partial responseaccording to RECIST (Version 1.1) criteria, as further defined herein.An exemplary effective treatment regimen of tivozanib is administrationof at least one treatment cycle with tivozanib, where a treatment cyclecomprises administering 1.5 mg tivozanib for 21 days followed by 7 dayswithout administration of tivozanib.

The methods and compositions described herein can be used alone or incombination with other therapeutic agents and/or modalities. The termadministered “in combination,” as used herein, is understood to meanthat two (or more) different treatments are delivered to the subjectduring the course of the subject's affliction with the disorder, suchthat the effects of the treatments on the patient overlap at a point intime. In certain embodiments, the delivery of one treatment is stilloccurring when the delivery of the second begins, so that there isoverlap in terms of administration. This is sometimes referred to hereinas “simultaneous” or “concurrent delivery.” In other embodiments, thedelivery of one treatment ends before the delivery of the othertreatment begins. In certain embodiments of either case, the treatmentis more effective because of combined administration. For example, thesecond treatment is more effective, e.g., an equivalent effect is seenwith less of the second treatment, or the second treatment reducessymptoms to a greater extent, than would be seen if the second treatmentwere administered in the absence of the first treatment, or theanalogous situation is seen with the first treatment. In certainembodiments, delivery is such that the reduction in a symptom, or otherparameter related to the disorder is greater than what would be observedwith one treatment delivered in the absence of the other. The effect ofthe two treatments can be partially additive, wholly additive, orgreater than additive. The delivery can be such that an effect of thefirst treatment delivered is still detectable when the second isdelivered.

II. Methods of Treatment

The invention involves methods of treating cancers, for example,difficult-to-treat cancers, such as renal cell carcinoma, withtivozanib. In one embodiment, tivozanib is used to treat renal cellcarcinoma where traditional first and second line therapies have failedto treat the cancer. In particular, the method of the invention issuitable for treating renal cell carcinoma in a subject as a third linetherapy. In one embodiment, the renal cell carcinoma is refractoryadvanced renal cell carcinoma. In another embodiment, the renal cellcarcinoma is metastatic. That is, the cancer cells have begun to migrateto other sites in the body, primarily through the blood and/or lymphaticsystems, and form new tumors which retain characteristics of theoriginal or primary tumors.

In modern clinical practice, it is becoming more common for subjects tobe treated by multiple anti-cancer therapies, both in combinations andsequentially. In one embodiment, the invention provides methods oftreating refractory cancer in a subject who has been previously treatedwith at least one prior therapy (e.g., a first line treatment). In oneembodiment, tivozanib may be administered subsequent to such first linetreatment (e.g., as second-line treatment). In another embodiment,tivozanib may be administered in combination with the first linetreatment, so that the refractory cancer may further respond to thefirst line treatment and/or respond to treatment with tivozanib. Inanother embodiment, tivozanib may be administered in combination with orprior to another treatment different from the first line treatment(e.g., second line treatment). The first and second line treatments maybe selected from a wide range of anti-cancer agents, including but notlimited to tyrosine kinase inhibitors (TKIs); VEGFR inhibitors(including anti-VEGFR antibodies and VEGFR TKIs); checkpoint inhibitors,and other systemic anti-cancer agents. In one embodiment, tivozanib maybe administered subsequent to such first and second-line treatments(e.g., as a third-line treatment). In another embodiment, tivozanib maybe administered in combination with one or both of the first and secondline treatments, so that the refractory cancer may further respond toone or more of the first and second line treatments and/or respond totreatment with tivozanib. In other embodiments, tivozanib may beadministered in combination with, or subsequent to additional lines oftreatment (e.g., as a fourth-line treatment, a fifth-line treatment,etc.).

In one embodiment, the invention provides methods of treating refractorycancer, such as advanced renal cell carcinoma, with tivozanib in asubject previously treated with at least one therapy (e.g., a first linetreatment). In one embodiment, the first line treatment is a TKI or aVEGFR TKI. In another embodiment, the first line treatment is acheckpoint inhibitor. In another embodiment, the first line treatment isa systemic anti-cancer agent other than a TKI or a checkpoint inhibitor.

In one embodiment, the invention provides methods of treating refractoryadvanced renal cell carcinoma with tivozanib in a subject previouslytreated with at least two therapies (e.g., a first line treatment and asecond line treatment). In one embodiment, the subject was previouslytreated with at least two different tyrosine kinase inhibitors (TKIs) orin particular, two or more vascular endothelial growth factor receptortyrosine kinase inhibitors (VEGFR TKI). In another embodiment, thesubject was previously treated with at least one TKI or VEGFR TKI and atleast one checkpoint inhibitor. In another embodiment, the subject waspreviously treated with at least one TKI or at least one VEGFR TKI andat least one other systemic anti-cancer agent. In another embodiment,the subject was previously treated with at least one checkpointinhibitor and at least one other systemic anti-cancer agent. In anotherembodiment, the subject was previously treated with at least two TKIs orVEGFR TKIs, and at least one checkpoint inhibitor.

In one embodiment, the invention provides methods of treating refractoryadvanced renal cell carcinoma in a subject identified as having afavorable or intermediate International Metastatic-RCC DatabaseConsortium (IMDC) risk score by administering tivozanib. For example, inone embodiment, the subject has a favorable risk score of 0. In anotherembodiment, the subject has an intermediate risk score of 1 or 2.

Refractory cancers according to the present invention can broadly be anytype of cancer, including, but not limited to, lung cancer, livercancer, ovarian cancer, prostate cancer, testicular cancer, gallbladdercancer, sarcoma, Ewing sarcoma, thyroid cancer, melanoma, skin cancer,pancreatic cancer; gastrointestinal/stomach (GIST) cancer, lymphoma,head and neck cancer, glioma or brain cancer, colon cancer, rectalcancer, breast cancer, renal cell carcinoma or kidney cancer. In oneembodiment, the refractory cancer is renal cell carcinoma.

A non-exhaustive list of TKIs with which a subject according to theinvention may be treated, or may have been previously treated, includeimatinib, gefitinib, erlotinib, sorafenib, dasatinib, sunitinib,lapatinib, nilotinib, pazopanib, crizotinib, alunbrig, vandetinib,vemurafenib, axitinib, bosutinib, cabozantinib, regorafenib, vismodegib,ponatinib, ibrutinib, acalabrutinib, alectinib, axinitib, or nintedanib.

A non-exhaustive list of VEGFR TKIs with which a subject according tothe invention may be treated, or may have been previously treated,include sunitinib, pazopanib, crizotinib, vandetinib, axitinib,cabozantinib, regorafenib, axinitib, or nintedanib. For purposes of thepresent invention, anti-VEGFR antibodies, such as bevacizumab, may beused in any instance where a VEGFR TKI inhibitor may be used, and thusmay substitute for a VEGF TKI in any of the methods of the presentinvention.

A non-exhaustive list of checkpoint inhibitors with which a subjectaccording to the invention may be treated, or may have been previouslytreated include the anti-PD1 antibodies nivolumab, pembrolizumab,cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab,toripalimab, prolgolimab cetrelimab, and pidilizumab; the anti-PDL1antibodies atezolizumab, durvalumab, avelumab or BMS-936559 (MDX-1105);and the anti-CTLA4 antibody ipilimumab.

A non-exhaustive list of other systemic anti-cancer agents with whichsubjects according to the invention may be treated, or may have beenpreviously treated include mTOR inhibitors, such as sirolimus,everolimus and temsirolimus; topoisomerase inhibitors, such asirinotecan and topotecan; platinum-based therapeutics, also referred toas platins, such as cisplatin, carboplatin, oxaliplatin and nedaplatin;taxanes, such as paclitaxel, docetaxel and cabazitaxel; poly ADP ribosepolymerase (PARP) inhibitors, such as olaparib, rucaparib and niraparib;anti-apoptotic protein inhibitors, such as venetoclax and blinatumomab;phosphatidylinositol 3 kinase (PI3K) inhibitors, such as idelalisib,copanlisib, buparlisib and duvelisib; proteasome inhibitors such asbortezomib, carfilzomib and ixazomib; HDAC inhibitors such asvorinostat, romidepsin, panobinostat and belinostat; CDK inhibitors suchas palbociclib, ribociclib and abemaciclib; growth factor antagonists,such as olaratumab, cetuximab, necitumumab, panitumumab and osimertinib;anti-tumor antigen antibodies, such as rituximab, ofatumumab,obinutuzumab, ibritumomab, daratumumab, dinutuximab, trastuzumab,ado-trastuzumab emtansine, pertuzumab, and brentuximab vedotin;aromatase inhibitors such as exemestane, anastazole and letrozole;hedgehog pathway inhibitors, such as sonidegib and vismodegib; folicacid inhibitors, such as pemetrexed; or nucleoside or microtubuleinhibitors that interfere with normal DNA synthesis, protein synthesis,cell replication, or otherwise inhibit rapidly proliferating cells. Suchnucleoside and microtubule inhibitors include trabectedin,mechlorethamine, vincristine, temozolomide, cytarabine, lomustine,azacitidine, omacetaxine mepesuccinate, asparaginase, eribulin mesylate,cabazitaxel, capacetrine, bendamustine, ixabepilone, nelarabine,clorafabine, and trifluridine/tipiracil.

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have an objective response rate (ORR) that is at least 5%, at least 10%,at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 100% greater than the baseline ORRof subjects receiving sorafenib (e.g., as a second or third linetreatment) or subjects receiving no treatment (e.g., no second or thirdline treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have an objective response rate (ORR) that is at least 1.25 times, atleast 1.50 times greater, at least 1.75 times, at least 2 times, atleast 2.25 times, or at least 2.50 times great than the baseline ORR ofsubjects receiving sorafenib (e.g., as a second or third line treatment)or subjects receiving no treatment (e.g., no second or third linetreatment). In one embodiment, subjects treated with tivozanib accordingto the methods of the invention (e.g., as a second or third linetreatment) have an ORR that is at least 2.25 times greater than thebaseline ORR of subjects receiving sorafenib (e.g., as a second or thirdline treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have a rate of progression-free survival (PFS) that is at least 5%, atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, or at least 100% greater than thebaseline rate of PFS of subjects receiving sorafenib (e.g., as a secondor third line treatment) or subjects receiving no treatment (e.g., nosecond or third line treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have a median progression-free survival (PFS) that is at least 1.25times, at least 1.50 times, at least 1.75 times, at least 2 times, atleast 2.25 times, or at least 2.50 times greater than the median PFS ofsubjects receiving sorafenib (e.g., as a second or third line treatment)or subjects receiving no treatment (e.g., no second or third linetreatment). In one embodiment, subjects treated with tivozanib accordingto the methods of the invention (e.g., as a second or third linetreatment) have a median PFS that is at least 2.25 times greater thanthe median PFS of subjects receiving sorafenib (e.g., as a second orthird line treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have a median progression-free survival (PFS) of at least one month, atleast two months, at least three months, at least four months, at least5 months, at least 6 months, at least 7 months, at least eight months,at least nine months, at least 10 months, at least 11 months, at least12 months, at least 13 months, at least 14 months, at least 15 months,at least 16 months, at least 17 months, at least 18 months, at least 19months, at least 20 months, at least 21 months, at least 22 months atleast 23 months, at least 24 months, at least 25 months, at least 26months, at least 27 months, at least 28 months, at least 29 months, atleast 30 months, at least 31 months, at least 32 months, at least 33months, at least 34 months, at least 35 months, at least 36 months, atleast 37 months, at least 38 months, at least 39 months, at least 40months, at least 41 months, at least 42 months, at least 43 months, atleast 44 months, at least 45 months, at least 46 months, at least 47months, at least 48 months, at least 49 months, at least 50 months, atleast 51 months, at least 52 months, at least 53 months, at least 54months, at least 55 months, at least 56 months, at least 57 months, atleast 58 months, at least 59 months, or at least 60 months longer thanthe median PFS for subjects receiving sorafenib (e.g., as a second orthird line treatment), or than subjects receiving no treatment (e.g., nosecond or third line treatment). In one embodiment, the medianprogression-free survival (PFS) is at least 5 months.

In one embodiment, subjects treated with tivozanib and previouslytreated with at least one checkpoint inhibitor according to the methodsof the invention have a median progression-free survival (PFS) of atleast one month, at least two months, at least three months, at leastfour months, at least 5 months, at least 6 months, at least 7 months, atleast eight months, at least nine months, at least 10 months, at least11 months, at least 12 months, at least 13 months, at least 14 months,at least 15 months, at least 16 months, at least 17 months, at least 18months, at least 19 months, at least 20 months, at least 21 months, atleast 22 months at least 23 months, at least 24 months, at least 25months, at least 26 months, at least 27 months, at least 28 months, atleast 29 months, at least 30 months, at least 31 months, at least 32months, at least 33 months, at least 34 months, at least 35 months, atleast 36 months, at least 37 months, at least 38 months, at least 39months, at least 40 months, at least 41 months, at least 42 months, atleast 43 months, at least 44 months, at least 45 months, at least 46months, at least 47 months, at least 48 months, at least 49 months, atleast 50 months, at least 51 months, at least 52 months, at least 53months, at least 54 months, at least 55 months, at least 56 months, atleast 57 months, at least 58 months, at least 59 months, or at least 60months longer than the median PFS for subjects receiving sorafenib, orthan subjects receiving no treatment. In one embodiment, the medianprogression-free survival (PFS) is at least 7 months.

In one embodiment, subjects treated with tivozanib and previouslytreated with one VEGFR TKI and one checkpoint inhibitor according to themethods of the invention have a median progression-free survival (PFS)of at least one month, at least two months, at least three months, atleast four months, at least 5 months, at least 6 months, at least 7months, at least eight months, at least nine months, at least 10 months,at least 11 months, at least 12 months, at least 13 months, at least 14months, at least 15 months, at least 16 months, at least 17 months, atleast 18 months, at least 19 months, at least 20 months, at least 21months, at least 22 months at least 23 months, at least 24 months, atleast 25 months, at least 26 months, at least 27 months, at least 28months, at least 29 months, at least 30 months, at least 31 months, atleast 32 months, at least 33 months, at least 34 months, at least 35months, at least 36 months, at least 37 months, at least 38 months, atleast 39 months, at least 40 months, at least 41 months, at least 42months, at least 43 months, at least 44 months, at least 45 months, atleast 46 months, at least 47 months, at least 48 months, at least 49months, at least 50 months, at least 51 months, at least 52 months, atleast 53 months, at least 54 months, at least 55 months, at least 56months, at least 57 months, at least 58 months, at least 59 months, orat least 60 months longer than the median PFS for subjects receivingsorafenib as a third line treatment, or than subjects receiving no thirdline treatment. In one embodiment, the median progression-free survival(PFS) is at least 7 months.

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have an overall survival (OS) rate that is at least 5%, at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 100% greater than the baseline OSrate of subjects receiving sorafenib (e.g., as a second or third linetreatment) or subjects receiving no treatment (e.g., no second or thirdline treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have a median overall survival (OS) rate of at least one month, at leasttwo months, at least three months, at least four months, at least 5months, at least 6 months, at least 7 months, at least eight months, atleast nine months, at least 10 months, at least 11 months, at least 12months, at least 13 months, at least 14 months, at least 15 months, atleast 16 months, at least 17 months, at least 18 months, at least 19months, at least 20 months, at least 21 months, at least 22 months atleast 23 months, at least 24 months, at least 25 months, at least 26months, at least 27 months, at least 28 months, at least 29 months, atleast 30 months, at least 31 months, at least 32 months, at least 33months, at least 34 months, at least 35 months, at least 36 months, atleast 37 months, at least 38 months, at least 39 months, at least 40months, at least 41 months, at least 42 months, at least 43 months, atleast 44 months, at least 45 months, at least 46 months, at least 47months, at least 48 months, at least 49 months, at least 50 months, atleast 51 months, at least 52 months, at least 53 months, at least 54months, at least 55 months, at least 56 months, at least 57 months, atleast 58 months, at least 59 months, or at least 60 months longer thanthe baseline median OS of subjects receiving sorafenib (e.g., as asecond or third line treatment), or than subjects receiving no treatment(e.g., no second or third line treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have a duration of response (DoR) that is at least 5%, at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, or at least 100% greater than the baseline DoRof subjects receiving sorafenib (e.g., as a second or third linetreatment) or subjects receiving no treatment (e.g., no second or thirdline treatment).

In one embodiment, subjects treated with tivozanib according to themethods of the invention (e.g., as a second or third line treatment)have a duration of response (DoR) that is at least one month, at leasttwo months, at least three months, at least four months, at least 5months, at least 6 months, at least 7 months, at least eight months, atleast nine months, at least 10 months, at least 11 months, at least 12months, at least 13 months, at least 14 months, at least 15 months, atleast 16 months, at least 17 months, at least 18 months, at least 19months, at least 20 months, at least 21 months, at least 22 months atleast 23 months, at least 24 months, at least 25 months, at least 26months, at least 27 months, at least 28 months, at least 29 months, atleast 30 months, at least 31 months, at least 32 months, at least 33months, at least 34 months, at least 35 months, at least 36 months, atleast 37 months, at least 38 months, at least 39 months, at least 40months, at least 41 months, at least 42 months, at least 43 months, atleast 44 months, at least 45 months, at least 46 months, at least 47months, at least 48 months, at least 49 months, at least 50 months, atleast 51 months, at least 52 months, at least 53 months, at least 54months, at least 55 months, at least 56 months, at least 57 months, atleast 58 months, at least 59 months, or at least 60 months longer thanthe baseline DoR of subjects receiving sorafenib (e.g., as a second orthird line treatment), or than subjects receiving no treatment (e.g., nosecond or third line treatment). In one embodiment, for subjects treatedwith tivozanib according to the methods of the invention, the 25thpercentile of the duration of response (DoR) is at least 9 months.

In one embodiment, subjects treated with tivozanib according to themethods of the invention have a median progression-free survival (PFS)of at least one month, at least two months, at least three months, atleast four months, at least 5 months, at least 6 months, at least 7months, at least eight months, at least nine months, at least 10 months,at least 11 months, at least 12 months, at least 13 months, at least 14months, at least 15 months, at least 16 months, at least 17 months, atleast 18 months, at least 19 months, at least 20 months, at least 21months, at least 22 months at least 23 months, at least 24 months, atleast 25 months, at least 26 months, at least 27 months, at least 28months, at least 29 months, at least 30 months, at least 31 months, atleast 32 months, at least 33 months, at least 34 months, at least 35months, at least 36 months, at least 37 months, at least 38 months, atleast 39 months, at least 40 months, at least 41 months, at least 42months, at least 43 months, at least 44 months, at least 45 months, atleast 46 months, at least 47 months, at least 48 months, at least 49months, at least 50 months, at least 51 months, at least 52 months, atleast 53 months, at least 54 months, at least 55 months, at least 56months, at least 57 months, at least 58 months, at least 59 months, orat least 60 months. In one embodiment, the median progression-freesurvival (PFS) is at least 5 months.

In one embodiment, subjects treated with tivozanib and previouslytreated with at least one checkpoint inhibitor according to the methodsof the invention have a median progression-free survival (PFS) of atleast one month, at least two months, at least three months, at leastfour months, at least 5 months, at least 6 months, at least 7 months, atleast eight months, at least nine months, at least 10 months, at least11 months, at least 12 months, at least 13 months, at least 14 months,at least 15 months, at least 16 months, at least 17 months, at least 18months, at least 19 months, at least 20 months, at least 21 months, atleast 22 months at least 23 months, at least 24 months, at least 25months, at least 26 months, at least 27 months, at least 28 months, atleast 29 months, at least 30 months, at least 31 months, at least 32months, at least 33 months, at least 34 months, at least 35 months, atleast 36 months, at least 37 months, at least 38 months, at least 39months, at least 40 months, at least 41 months, at least 42 months, atleast 43 months, at least 44 months, at least 45 months, at least 46months, at least 47 months, at least 48 months, at least 49 months, atleast 50 months, at least 51 months, at least 52 months, at least 53months, at least 54 months, at least 55 months, at least 56 months, atleast 57 months, at least 58 months, at least 59 months, or at least 60months. In one embodiment, the median progression-free survival (PFS) isat least 7 months.

In one embodiment, subjects treated with tivozanib and previouslytreated with one VEGFR TKI and one checkpoint inhibitor according to themethods of the invention have a median progression-free survival (PFS)of at least one month, at least two months, at least three months, atleast four months, at least 5 months, at least 6 months, at least 7months, at least eight months, at least nine months, at least 10 months,at least 11 months, at least 12 months, at least 13 months, at least 14months, at least 15 months, at least 16 months, at least 17 months, atleast 18 months, at least 19 months, at least 20 months, at least 21months, at least 22 months at least 23 months, at least 24 months, atleast 25 months, at least 26 months, at least 27 months, at least 28months, at least 29 months, at least 30 months, at least 31 months, atleast 32 months, at least 33 months, at least 34 months, at least 35months, at least 36 months, at least 37 months, at least 38 months, atleast 39 months, at least 40 months, at least 41 months, at least 42months, at least 43 months, at least 44 months, at least 45 months, atleast 46 months, at least 47 months, at least 48 months, at least 49months, at least 50 months, at least 51 months, at least 52 months, atleast 53 months, at least 54 months, at least 55 months, at least 56months, at least 57 months, at least 58 months, at least 59 months, orat least 60 months. In one embodiment, the median progression-freesurvival (PFS) is at least 7 months.

In one embodiment, subjects treated with tivozanib according to themethods of the invention have a duration of response (DoR) that is atleast one month, at least two months, at least three months, at leastfour months, at least 5 months, at least 6 months, at least 7 months, atleast eight months, at least nine months, at least 10 months, at least11 months, at least 12 months, at least 13 months, at least 14 months,at least 15 months, at least 16 months, at least 17 months, at least 18months, at least 19 months, at least 20 months, at least 21 months, atleast 22 months at least 23 months, at least 24 months, at least 25months, at least 26 months, at least 27 months, at least 28 months, atleast 29 months, at least 30 months, at least 31 months, at least 32months, at least 33 months, at least 34 months, at least 35 months, atleast 36 months, at least 37 months, at least 38 months, at least 39months, at least 40 months, at least 41 months, at least 42 months, atleast 43 months, at least 44 months, at least 45 months, at least 46months, at least 47 months, at least 48 months, at least 49 months, atleast 50 months, at least 51 months, at least 52 months, at least 53months, at least 54 months, at least 55 months, at least 56 months, atleast 57 months, at least 58 months, at least 59 months, or at least 60months.

According to certain embodiments of the invention, treatment withtivozanib is indicated as long as a clinical benefit is observed in thesubject or until unacceptable toxicity occurs.

III. Dosage

Exemplary effective amounts, dosages, or treatment regimens of tivozanibinclude 0.5-3 mg, 0.5-2 mg, 1-3 mg, 0.5-1.5 mg, 1.0-2.0 mg, 1.0-1.5 mg.1.4-1.6 mg, 0.8-0.9 mg, 0.9-1.0 mg, 0.9-1.1 mg, 1.0-1.1 mg, 1.1-1.2 mg,1.2-1.3 mg, 1.3-1.4 mg, 1.4-1.5 mg, 1.4-1.6 mg, 1.5-1.6 mg, 1.6-1.7 mg,1.7-1.8 mg, 1.8-1.9 mg, 1.8-2.0 mg or 1.9-2.0 mg daily or every otherday.

The amount administered will depend on variables such as the type andextent of disease or indication to be treated, the overall health of thepatient, the pharmaceutical formulation, and the route ofadministration. The initial dosage can be increased beyond the upperlevel in order to rapidly achieve the desired blood-level ortissue-level. Alternatively, the initial dosage can be smaller than theoptimum, and the daily dosage may be progressively increased during thecourse of treatment. Human dosage can be optimized, e.g., in aconventional Phase I dose escalation study. Dosing frequency can vary,depending on factors such as route of administration, dosage amount, andthe disease being treated. Exemplary dosing frequencies are once perday, once every other day, once every three days, once every four days,once every five days, once every six days, once per week and once everytwo weeks.

In one embodiment, the dosage of tivozanib is 1.5 mg daily. In anotherembodiment, the dosage is 1.0 mg daily. Additional exemplary effectiveamounts, dosages, or treatment regimens of tivozanib are described inU.S. Pat. Nos. 6,821,987, and 7,166,722.

According to one embodiment, the dosage is 1.0 mg daily of tivozanibhydrochloride (equivalent to 0.89 mg tivozanib free base). According toanother embodiment, the dosage is 1.5 mg daily of tivozanibhydrochloride (equivalent to 1.34 mg tivozanib free base). In oneembodiment, the dose is 1.34 mg daily of tivozanib free base. In anotherembodiment, the dose is 0.89 mg daily of tivozanib free base.

According to one embodiment, a 1.5 mg daily dose of tivozanib is reducedto 1.0 mg daily when a subject experiences a ≥Grade 3 drug-relatedadverse event.

According to one embodiment, a 1.5 mg daily dose of tivozanib is reducedto 1.5 mg every other day for a subject experiencing moderate hepaticimpairment (Child-Pugh class B).

According to one embodiment, a 1.5 mg daily dose of tivozanib is reducedto 1.0 mg every other day for a subject experiencing severe hepaticimpairment (Child-Pugh class C).

In one embodiment, the dose is 1.5 mg daily of tivozanib hydrochlorideadministered for 21 days followed by 7 days without administration.

IV. Administration Protocol

Tivozanib may be administered as an oral tablet or capsule or as anintravenous (IV) infusion. When administered as an oral tablet orcapsule, the dosage of tivozanib may be provided in a single capsule ortablet or in two or more capsules or tablets.

Exemplary effective amounts, dosages, or treatment regimens of tivozanibinclude administration on a repeating schedule of one dose (e.g., asingle dosage contains 0.5-2.0 mg of tivozanib) per day for three weeks,followed by one week off (i.e., 3 weeks on, 1 week off). For example,tivozanib may be administered on a repeating schedule of 0.5-3 mg, 0.5-2mg, 0.5-1.5 mg, 1.0-3.0 mg, 1.0-2.0 mg, 1.0-1.5 mg, or 1.4-1.6 mg perday for three weeks, followed by one week off (i.e., 3 weeks on, 1 weekoff). The period of time beginning from Day 1 of administration to thelast day of the week off may be referred to as a treatment cycle. Inother embodiments, tivozanib may be administered as one dose (e.g., asingle dosage contains 0.5-2.0 mg of tivozanib) per day. For example,tivozanib may be administered at a dose of 0.5-3 mg, 0.5-2 mg, 0.5-1.5mg, 1.0-3.0 mg, 1.0-2.0 mg, 1.0-1.5 mg or 1.4-1.6 mg, 1 mg, or 1.5 mgdaily.

In one embodiment, tivozanib is administered in an amount of 1.5 mg perday. In another embodiment, tivozanib is administered in an amount of1.0 mg per day. In another embodiment, tivozanib is administered in anamount of 1.5 mg per day every day for three weeks (i.e., 21 days),followed by one week (i.e., 7 days) with no dose of tivozanib (i.e., 3weeks on, 1 week off), where three weeks on tivozanib and one week offconstitutes a 4 week treatment cycle.

In one embodiment, tivozanib is orally administered in an amount of 1.5mg daily for three weeks, followed by one week off, while in anotherembodiment, tivozanib is administered in an amount of 1.0 mg daily forthree weeks, followed by one week without administration of tivozanib.According to these embodiments, three weeks on and one week offconstitutes a 4 week treatment cycle.

In one embodiment, tivozanib is orally administered in an amount of 1.5mg daily and reduced to 1.0 mg daily when the subject experiences a≥Grade 3 drug-related adverse event. In this embodiment, theadministration period for tivozanib is three weeks (starting from thefirst 1.5 mg dose), followed by one week without administration oftivozanib. According to this embodiment, three weeks on and one week offconstitutes a 4-week treatment cycle.

In one embodiment, tivozanib is orally administered in an amount of 1.5mg daily and is reduced to 1.5 mg every other day when the subjectdevelops moderate hepatic impairment (Child-Pugh Class B). In thisembodiment, the administration period is 3 weeks (starting from thefirst 1.5 mg dose) followed by one week without administration.According to this embodiment, three weeks on and one week offconstitutes a 4-week treatment cycle.

In one embodiment, tivozanib is orally administered in an amount of 1.5mg daily and is reduced to 1.0 mg every other day when a subjectdevelops severe hepatic impairment (Child-Pugh Class C). In thisembodiment, the administration period is 3 weeks followed by one weekwithout administration. According to this embodiment, three weeks on andone week off constitutes a 4-week treatment cycle.

According to one embodiment, a subject undergoes one, two, three, four,five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36treatment cycles of tivozanib, for example, four-week treatment cyclesof tivozanib, for example, where the treatment cycle is three weeks on,one week off. According to one embodiment, a treatment cycle (forexample, a four-week treatment cycle) is repeated as long as the subjectexperiences a clinical benefit or until the subject experiencesunacceptable toxicity.

In a further embodiment, tivozanib is administered as a capsule. In afurther embodiment, the capsule contains gelatin. In yet anotherembodiment, the capsule contains gelatin and titanium dioxide.

In a further embodiment, tivozanib is formulated as a pharmaceuticalcomposition with mannitol and magnesium stearate. In other embodiments,other pharmaceutically acceptable carriers may be used.

Throughout the description, where compositions are described as having,including, or comprising specific components, or where processes andmethods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions ofthe present invention that consist essentially of, or consist of, therecited components, and that there are processes and methods accordingto the present invention that consist essentially of, or consist of, therecited processing steps.

In the application, where an element or component is said to be includedin and/or selected from a list of recited elements or components, itshould be understood that the element or component can be any one of therecited elements or components, or the element or component can beselected from a group consisting of two or more of the recited elementsor components.

Further, it should be understood that elements and/or features of acomposition or a method described herein can be combined in a variety ofways without departing from the spirit and scope of the presentinvention, whether explicit or implicit herein. For example, wherereference is made to a particular compound, that compound can be used invarious embodiments of compositions of the present invention and/or inmethods of the present invention, unless otherwise understood from thecontext. In other words, within this application, embodiments have beendescribed and depicted in a way that enables a clear and conciseapplication to be written and drawn, but it is intended and will beappreciated that embodiments may be variously combined or separatedwithout parting from the present teachings and invention(s). Forexample, it will be appreciated that all features described and depictedherein can be applicable to all aspects of the invention(s) describedand depicted herein.

It should be understood that the expression “at least one of” includesindividually each of the recited objects after the expression and thevarious combinations of two or more of the recited objects unlessotherwise understood from the context and use. The expression “and/or”in connection with three or more recited objects should be understood tohave the same meaning unless otherwise understood from the context.

The use of the term “include,” “includes,” “including,” “have,” “has,”“having,” “contain,” “contains,” or “containing,” including grammaticalequivalents thereof, should be understood generally as open-ended andnon-limiting, for example, not excluding additional unrecited elementsor steps, unless otherwise specifically stated or understood from thecontext.

Where the use of the term “about” is before a quantitative value, thepresent invention also includes the specific quantitative value itself,unless specifically stated otherwise. As used herein, the term “about”refers to a ±10% variation from the nominal value unless otherwiseindicated or inferred.

It should be understood that the order of steps or order for performingcertain actions is immaterial so long as the present invention remainoperable. Moreover, two or more steps or actions may be conductedsimultaneously.

The use of any and all examples, or exemplary language herein, forexample, “such as” or “including,” is intended merely to illustratebetter the present invention and does not pose a limitation on the scopeof the invention unless claimed. No language in the specification shouldbe construed as indicating any non-claimed element as essential to thepractice of the present invention.

Examples

The invention is further illustrated by the following examples. Thefollowing examples are provided for illustration purposes only, and arenot to be construed as limiting the scope or content of the invention inany way.

1. Phase 3 Clinical Trial Demonstrates Tivozanib's Beneficial Effects inTreating Refractory Advanced RCC

a. Study Design

A randomized, controlled, open-label, multi-center Phase 3 studycomparing treatment with tivozanib to treatment with sorafenib withrefractory advanced renal cell carcinoma (RCC) was undertaken. Sorafenibwas chosen as the comparator for this Phase 3 trial because it is aVEGFR inhibitor that is approved for treatment of advanced RCC, and hasbeen previously evaluated in prior clinical studies in the refractorysetting.

Subjects were randomized (1:1) to treatment with tivozanib or sorafenib.The randomization of subjects was stratified according to theInternational Metastatic Renal Cell Carcinoma Database Consortium (IMDC)risk category (favorable, intermediate, poor) and according to priortherapy which could be: 1) two prior VEGFR TKIs; 2) a check pointinhibitor (e.g., a PD-1 or PDL-1 inhibitor) and a prior VEGFR TKI; or 3)a VEGFR TKI plus any other systemic agent. Once the strata wereidentified, treatment was randomly assigned to a subject with the stratausing a complete permuted block design in an unblended fashion(open-label). In the event a subject had previously received treatmentwith two VEGFR TKIs and a checkpoint inhibitor, the patient wasstratified according to the most recent line of therapy.

The maximum tolerated dose (MTD) of tivozanib was determined to be 1.5mg/day based on data from a previous study KRN951/03-B01, where 3 of 8subjects in the 2 mg/day tivozanib group experienced a dose limitingtoxicity (DLT), indicating that the maximum tolerated dose had beenexceeded. The safety of the MTD of 1.5 mg/day was confirmed in multiplesubsequent studies. In that same study, it was determined thattoxicities were rapidly reversible upon stopping treatment withtivozanib.

The dosing regimen for the Phase 3 trial was 1.5 mg/day givencontinuously for 21 days followed by a 7-day break, i.e., 3 weeks on, 1week off. This dose was shown to be well tolerated in study subjectsenrolled in a previous study AV-951-07-201, where only 8.5% (23/272)study subjects required a dose reduction and only 2.9% (8/272) requireda dose interruption. The 7-day break was utilized in an effort tomaximize clinical benefit while giving study subject an opportunity torecover from any toxicities.

b. Study Objectives and Purpose

The primary objective of the Phase 3 Trial was to compare theprogression-free survival (PFS) of subjects with refractory advanced RCCrandomized to treatment with tivozanib or sorafenib as assessed byblinded independent radiological review (IRR) of computerized tomography(CT) and/or magnetic resonance imaging (MRI).

The secondary objectives of this study were (1) to compare the overallsurvival (OS) of subjects randomized to treatment with tivozanib orsorafenib; (2) to compare objective response rate (ORR) and duration ofresponse (DoR) of subjects randomized to treatment with tivozanib orsorafenib; and (3) to compare the safety and tolerability of tivozaniband sorafenib.

Tertiary objectives of this study were to explore any relationshipbetween tivozanib and sorafenib drug levels and activity and tivozaniband sorafenib drug levels and adverse events (AEs).

c. Subject Inclusion Criteria and Enrollment

Subjects were enrolled beginning approximately June 2016 through August2017. A total of approximately 350 subjects were enrolled, of whichapproximately 343 were randomized for treatment with either tivozanib orsorafenib. The study was open to males and females meeting the followingeligibility criteria:

-   -   1. At least 18 years of age.    -   2. Subjects with metastatic RCC who have failed 2 or 3 prior        systemic regimens, one of which includes a VEGFR TKI other than        sorafenib or tivozanib.        -   a. Postoperative or adjuvant systemic therapy was not            counted as a prior therapy unless recurrence was detected            within 6 months of completion of treatment, in which case it            was counted as a prior therapy for metastatic disease.        -   b. Subjects had to be off all systemic anti-cancer therapy            or radiotherapy for at least 2 weeks prior to Cycle 1 Day 1.    -   3. Subjects must have recovered from the adverse events (AEs) of        prior therapy or returned to baseline. Controlled AEs such as        hypothyroidism or hypertension were permitted.    -   4. Histologically or cytologically confirmed RCC with a clear        cell component (subjects with pure papillary cell tumor or other        non-clear cell histologies, including collecting duct,        medullary, chromophobe, and unclassified RCC were excluded).    -   5. Measurable disease per the RECIST criteria (Version 1.1).    -   6. ECOG performance status of 0 or 1.    -   7. Life expectancy ≥3 months.

d. Tivozanib Administration

Tivozanib hydrochloride was administered orally, at a dose of 1.5mg/day, beginning on Day 1 of Cycle 1. Subjects received tivozanib oncedaily for 3 weeks followed by 1 week off the study drug (1 cycle=3 weekson, 1 week off). One cycle was defined as 4 weeks of treatment. Cycleswere repeated every 4 weeks. Tivozanib was administered as a 1.5 mgcapsule that was to be swallowed whole without crushing or opening.

The prescribed daily dose of tivozanib was taken, preferably in themorning, with water. Tivozanib was taken at least 1 hour before or 2hours after ingesting any food or other medications. Grapefruit juicewas contraindicated during the study. Treatment with tivozanib wascontinued if tolerated and in the absence of documented diseaseprogression. If a dose was vomited or if a dose was missed for anyreason, the dose was not made up. If Day 1 of a cycle was delayed forany reason, the complete 21 days of tivozanib were administered once thecycle started. Only one tivozanib capsule (1.5 mg) was taken each day.

Dose reductions of tivozanib to 1.0 mg/day were allowed for subjectswith ≥Grade 3 drug-related adverse events. The exception washypertension, which was treated with anti-hypertensive drugs prior todose reduction. Once the dose of tivozanib was reduced, it could not bere-escalated throughout the study. If a subject was unable to tolerate adose of 1.0 mg/day due to toxicities thought to be related to tivozanib,dosing with tivozanib was discontinued.

Subjects with Grade 4 drug-related toxicity, or Grade 3 drug-relatedtoxicity that was persistent despite appropriate medical care, had theirdose interrupted to allow for resolution of the toxicity. Tivozanibadministration was permitted to be interrupted for up to 4 weeks. If asubject was able to resume treatment after interruption of ≤4 weeks,missed doses were not made up (i.e., cycle duration will remainunchanged). If any drug-related toxicity resulted in an interruptionof >4 weeks, the subject was discontinued from the study unless therewas a clear benefit from treatment.

e. Duration of Treatment

Subjects with documented stable disease or an objective response werepermitted to receive therapy at the same dose and schedule until diseaseprogression or unacceptable toxicities occurred, or if other withdrawalcriteria were met.

Subjects experiencing unacceptable toxicities were discontinued fromfurther study treatment. Subjects with radiological evidence ofprogressive disease (per RECIST Version 1.1) per investigator/localradiology assessment continued treatment until progressive disease wasverified by an independent radiologist. Verification of progressivedisease was not required when a patient demonstrated significantclinical deterioration that is compatible with progressive disease.Subjects with documented disease progression (as verified by anindependent radiologist) were discontinued from the study treatment.

f. Analysis of Endpoints

Three populations were used in the analyses of the data:

-   -   1. The intent-to-treat (ITT) population which consisted of all        randomized subjects; this population was used for efficacy        analysis, including primary endpoint (progression-free        survival). Subjects were analyzed as randomized.    -   2. The per protocol (PP) population which was defined as all        randomized subjects who received at least two cycles (8 weeks)        of protocol treatment (unless discontinued due to death or        disease progression), had no major protocol deviations that        confounded the effects of treatment, and met all eligibility        criteria. Major protocol deviations included but were not        limited to failure to satisfy eligibility criteria and taking        prohibited medications during the treatment phase of the study.        Subjects were analyzed as treated.    -   3. The safety population (SAF) which included all subjects who        received at least one dose of either study drug. Subjects were        analyzed as treated.

The primary efficacy endpoint (PFS) and secondary efficacy endpoints(OS, ORR, and DoR) analyses were carried out using the ITT population.The primary efficacy endpoint of PFS also was analyzed using the PPpopulation.

The primary analysis was to compare the PFS of subjects dosed withtivozanib with those subjects dosed with sorafenib. The null hypothesiswas that the median tivozanib PFS would be equal to that of sorafeniband the alternative hypothesis was that the two PFS medians would not beequal. The IRR was the primary data source for the PFS analysis.

The primary analysis was carried out by using a stratified Log-Ranktest, in which the stratification factors were IMDC risk category(favorable; intermediate; poor) and prior therapy (two prior VEGFR TKIs;a prior checkpoint inhibitor (PD-1 or PD1 L inhibitor) plus a priorVEGFR TKI; a prior VEGFR TKI plus any other systemic agent), and using atwo-sided 5% significance level. The distribution of the PFS wasestimated using the Kaplan-Meier method. The median event time and2-sided 95% confidence interval for the median was also determined.

i) Analysis of Endpoints: Progression-Free Survival (PFS)

The results for the primary endpoint are shown in FIG. 1, and weredetermined as follows: after approximately 255 events, defined underRECIST to mean either tumor progression or death, subjects wereevaluated for progression-free survival (PFS) by independent radiologicreview. Primary analysis performed was by stratified log-rank test. Asshown in FIG. 1 and FIG. 6, subjects receiving tivozanib had a medianPFS of 5.59 months, compared to a median PFS of 3.88 months for thosesubjects receiving sorafenib. The stratified log rank probabilityp-value was 0.0165, indicating a statistically significant difference.

ii) Subgroup Analyses of Progression Free Survival (PFS)

Subgroup analysis of PFS rates were conducted stratified by priortherapy. As shown in FIG. 5, median PFS for the subset of patientsreceiving a prior check point inhibitor was 7.29 months for thetivozanib arm, whereas the median PFS for the sorafenib arm was only5.91 months. Additional subgroup analyses of PFS for the ITT populationwere conducted using a Cox Model as shown in FIG. 10. A forest plotincluding hazard ratios (HR) with 95% confidence intervals for eachsubgroup is depicted in FIG. 9. A hazard ratio, including its errorrange, of less than 1.0 (falling entirely to the left of the verticaldotted line at HR=1.0 in FIG. 9), indicates that treatment withtivozanib demonstrated a statistically significant benefit in PFScompared with treatment with sorafenib. As shown, the hazard ratios forthe subgroups of patients receiving prior therapy with two VEGFR TKIs(HR=0.57) or prior therapy with a checkpoint inhibitor plus a VEGFR TKI(HR=0.55) fall entirely to the left of the vertical dotted line,indicating that in these subgroups subjects receiving tivozanibexperienced a statistically significant benefit in PFS compared tosubjects receiving sorafenib. Further, the hazard ratios for thesubgroups of patients with an IMDC Risk Category “Favorable” (HR=0.46)and “Intermediate” (HR=0.69) likewise fell entirely to the left of thevertical dotted, indicating that in these subgroups subjects receivingtivozanib experienced a statistically significant benefit in PFScompared to subjects receiving sorafenib.

The secondary endpoints (OS, ORR, and DoR) were analyzed using theinvestigator and independent radiological review assessments. The degreeof agreement between the investigator and the independent assessment ofresponses was also determined.

iii) Analysis of Endpoints: Overall Survival (OS)

An OS analysis was carried out two years after the final patientenrollment. Secondary analysis was performed was by stratified log-ranktest. Kaplan-Meier analyses of overall survival are shown in FIGS. 2 and7, which show that subjects receiving tivozanib had a median OS of 16.39months, compared to a median OS of 19.65 months for those subjectsreceiving sorafenib. The HR was 0.99 and the stratified log rankprobability p-value was 0.9501. Thus, no statistically significantdifference was observed in OS between the two treatment groups.

iv) Subgroup Analysis of Overall Survival

Additional subgroup analyses of OS for the ITT population were conductedusing a Cox Model as shown in FIG. 12. A forest plot including hazardratios (HR) with 95% confidence intervals for each subgroup is depictedin FIG. 11. The hazard ratios with confidence intervals do not indicatea statistically significant difference in OS between subjects receivingtivozanib or sorafenib. It should be noted, however, that the OSanalysis was not controlled for any subsequent therapy afterprogression.

v) Analysis of Endpoints: Objective Response Rate (ORR)

The proportion of subjects achieving confirmed ORR (complete response[CR]+partial response [PR]) was summarized by treatment arms and cycleand was compared between the two treatment arms using theCochran-Mantel-Haenszel (CMH) test with the same stratification factorsused for the PFS analysis. As shown in FIG. 3, subjects receivingtivozanib showed an ORR of 18.0 percent (31 PR/172 subjects), comparedto an ORR of 8.0 percent (14 PR/175 subjects) for subjects receivingsorafenib.

Analysis of ORR was also conducted for subgroups stratified by priortherapy. As shown in FIG. 12, 79 subjects receiving tivozanib and 80subjects receiving sorafenib received two prior VEGFR TKI treatments; 47subjects receiving tivozanib and 44 subjects receiving sorafenibreceived prior therapy with a checkpoint inhibitor plus a VEGF TKI; and48 subjects receiving tivozanib and 51 subjects receiving sorafenibreceived prior therapy with a VEGFR TKI plus any other systemic agent.

The results are shown in FIG. 13, where the data show a trend towards abenefit in ORR for subjects in the tivozanib arm versus subjects in thesorafenib arm in all three subgroups. For subjects who received priortherapy with two VEGFR TKIs, the ORR was 15.2% (12 PR/79 subjects) inthe tivozanib arm versus 7.5% (6 PR/80 subjects) in the sorafenib arm.For subjects receiving prior therapy with a checkpoint inhibitor and aprior VEGF TKI, the ORR was 24.4% (11 PR/45 subjects) in the tivozanibarm versus 6.8% (3 PR/44 subjects) in the sorafenib arm. For subjectsreceiving prior therapy with a VEGFR TKI plus any other systemic agent,the ORR was 16.7% (8 PR/48 subjects) in the tivozanib arm versus 9.8% (5PR/51 subjects) in the sorafenib arm.

vi) Analysis of Endpoints: Duration of response (DoR)

The DoR was analyzed using the same method as the progression-freesurvival analysis. The data are shown in FIG. 14. DoR was onlycalculated for the subgroup of subjects with an objective tumor response(PR or CR). Thus the sample size for both the tivozanib and sorafenibarms was small. While the results were not statistically significant, inpart due to the small sample size, the data show a trend in duration ofresponse favoring tivozanib over sorafenib (1st quartile=9.79 months fortivozanib as compared to 1st quartile=5.55 months for sorafenib).

vii) Subjects Treated with Prior Checkpoint Inhibitor: 1-YearProbability of Survival

A subset of subjects who had been treated with at least one priorcheckpoint inhibitor at any time prior to the study treatment (forexample, whether as a first, second, or third line therapy) were alsoanalyzed. For those subjects who received a prior checkpoint inhibitor,a clear difference (unstratified Log-rank p-value=0.0616) was observedin PFS between those subjects who received tivozanib (n=52) and thosewho received sorafenib (n=46). As shown in FIG. 5, the median PFS forthis subset of subjects was 7.29 months for the tivozanib arm ascompared to 5.91 months for the sorafenib arm. Further, as shown in FIG.5, subjects receiving tivozanib after prior anti-cancer therapy with acheckpoint inhibitor were determined to have a 0.37 (˜37%) 1-yearprobability of survival, compared to a 1-year probability of survival of0.05 (˜5%) for subjects receiving sorafenib after prior anti-cancertherapy after prior treatment with a checkpoint inhibitor.

As shown in FIG. 8, no statistically significant differences wereobserved for OS in this subset between the two treatment groups(unstratified Log-rank p-value=0.8360).

viii) Safety Analyses: Summary of Adverse Events

Additional analyses included the incidence of adverse events emergingduring treatment. Not all differences observed between the tivozanib andsorafenib treatment arms were statistically significant. However, asshown in Table 1, subjects in the tivozanib treatment arm exhibitedlower incidence of adverse events leading to treatment discontinuation,dose reduction, and dose interruption, as well as lower incidence oftreatment emergent adverse events of Grade 3 or higher.

TABLE 1 Tivozanib Sorafenib Total (N = 173) (N = 170) (N = 343) n (%) n(%) n (%) Patients with At Least One Treatment- 171 (98.8) 170 (100.0)341 (99.4) Emergent AE Patients with At Least One Treatment- 36 (20.8)50 (29.4) 86 (25.1) Emergent AE Leading to Treatment DiscontinuationPatients with At Least One Treatment- 41 (23.7) 65 (38.2) 106 (30.9)Emergent AE Leading to Dose Reduction Patients with At Least OneTreatment- 83 (48.0) 107 (62.9) 190 (55.4) Emergent AE Leading to DoseInterruption Patients with At Least One Treatment- 72 (41.6) 65 (38.2)137 (39.9) Emergent SAE Patients with At Least One Treatment- 146 (84.4)160 (94.1) 306 (89.2) Related Treatment-Emergent AE Patients with AtLeast one Grade >= 127 (73.4) 137 (80.6) 264 (77.0) 3 Treatment-EmergentAE Patients with At Least one Grade >= 76 (43.9) 93 (54.7) 169 (49.3) 3Treatment-Related Treatment-Emergent AE Patients with at Least OneTreatment- 16 (9.2) 13 (7.6) 29 (8.5) Emergent AE Leading to DeathAbbreviations: SAF = Safety; AE = Adverse Event; SAE = Serious AdverseEvent.

Accordingly, the data suggest that tivozanib is superior to sorafenib interms of reducing the number of dose reduction, dose interruption, andtreatment discontinuation due to adverse events emerging duringtreatment.

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles cited herein is incorporated by reference for all purposes.

EQUIVALENTS

The invention can be embodied in other specific forms with departingfrom the essential characteristics thereof. The foregoing embodimentstherefore are to be considered illustrative rather than limiting on theinvention described herein. The scope of the invention is indicated bythe appended claims rather than by the foregoing description, and allchanges that come within the meaning and range of equivalency of theclaims are intended to be embraced therein.

We claim:
 1. A method of treating a subject suffering from refractory cancer wherein the subject has previously been treated with at least one anti-cancer therapy, the method comprising administering to the subject an effective amount of tivozanib.
 2. A method of treating a subject suffering from refractory renal cell carcinoma wherein the subject has previously been treated with at least one anti-cancer therapy, the method comprising administering to the subject an effective amount of tivozanib.
 3. The method of claim 1 or 2, wherein the method comprises administering to the subject a pharmaceutical composition comprising 1.5 mg tivozanib for 21 days followed by 7 days without administration of tivozanib, wherein administering the tivozanib for 21 days followed by 7 days without administration constitutes a treatment cycle.
 4. A method of treating a subject suffering from refractory cancer wherein the subject has previously been treated with at least one anti-cancer therapy, comprising administering to the subject a pharmaceutical composition comprising 1.5 mg tivozanib for 21 days followed by 7 days without administration of tivozanib, wherein administering the tivozanib for 21 days followed by 7 days without administration constitutes a treatment cycle.
 5. A method of treating a subject suffering from refractory renal cell carcinoma wherein the subject has previously been treated with at least one anti-cancer therapy comprising administering to the subject a pharmaceutical composition comprising 1.5 mg tivozanib for 21 days followed by 7 days without administration of tivozanib, wherein administering the tivozanib for 21 days followed by 7 days without administration constitutes a treatment cycle.
 6. The method of any one of claims 1-5, wherein: (a) the subject has previously been treated with at least one checkpoint inhibitor; (b) the subject has previously been treated with at least one vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI); (c) the subject has previously been treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) and a checkpoint inhibitor; or (d) the subject has previously been treated with two vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI).
 7. The method of any one of claims 1-6, wherein the subject was previously treated with at least a first line anti-cancer therapy and a second line anti-cancer therapy.
 8. The method of claim 7, wherein the first line and second line anti-cancer therapies were both vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) therapies.
 9. The method of claim 7, wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a checkpoint inhibitor.
 10. The method of claim 7, wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a systemic anti-cancer agent.
 11. The method of claim 7, wherein the first line and second line anti-cancer therapies were selected from a checkpoint inhibitor and a systemic anti-cancer agent.
 12. A method of treating a subject suffering from refractory renal cell carcinoma comprising administering to the subject an effective amount of tivozanib in combination with a checkpoint inhibitor.
 13. The method of claim 12, wherein tivozanib is administered concurrent with the checkpoint inhibitor.
 14. The method of claim 12, wherein tivozanib is administered subsequent to the checkpoint inhibitor.
 15. The method of any one of claims 1-14, wherein the subject is identified as having an International Metastatic-RCC Database Consortium (IMDC) risk score of favorable or intermediate prior to treating the subject.
 16. The method of claim 15, wherein the IMDC risk category is favorable.
 17. The method of claim 15, wherein the IMDC risk category is intermediate.
 18. The method of any one of claim 1, 3, 4, or 6-17, wherein the refractory cancer is refractory renal cell carcinoma (RCC).
 19. The method of any one of claims 1-18, wherein the tivozanib is tivozanib hydrochloride monohydrate.
 20. The method of any one of claims 1-19, wherein the subject undergoes one or more treatment cycles with tivozanib.
 21. The method of any one of claim 6 or 8-10, wherein the VEGFR TKI is sunitinib, sorafenib, pazopanib, crizotinib, vandetinib, axitinib, cabozantinib, regorafenib, axinitib, or nintedanib.
 22. The method of any one of claim 6, 9, or 11-14, wherein the checkpoint inhibitor is an anti-PDL1 or anti-PD1 inhibitor.
 23. The method of claim 22, wherein the checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, prolgolimab cetrelimab, pidilizumab, BMS-936559, MDX-1105, atezolizumab, durvalumab, or avelumab.
 24. The method of claim 10 or 11, wherein the systemic anti-cancer-agent is everolimus or temsirolimus.
 25. The method of any one of claims 1-24, wherein the subject exhibits a complete or partial response to tivozanib after one treatment cycle, after two treatment cycles, after three treatment cycles, after four treatment cycles or after five treatment cycles.
 26. The method of any one of claims 1-25, wherein the subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more than twelve treatment cycles.
 27. The method of any one of claims 1-26, wherein the dose of tivozanib is reduced when a subject experiences a ≥Grade 3 drug-related adverse event.
 28. The method of any one of claims 1-26, wherein the dose of tivozanib is reduced for a subject experiencing moderate hepatic impairment (Child-Pugh class B).
 29. The method of any one of claims 1-26, wherein the dose of tivozanib is reduced for a subject experiencing severe hepatic impairment (Child-Pugh class C).
 30. The method of any one of claim 27-29, wherein the dose is reduced to 1.0 mg daily.
 31. The method of any one of claims 27-29, wherein the dose is reduced to 1.5 mg every other day.
 32. The method of any one of claims 27-29, wherein the dose is reduced to 1.0 mg every other day.
 33. A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory cancer, wherein the subject has previously been treated with at least one anti-cancer therapy.
 34. A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory renal cell carcinoma, wherein the subject has previously been treated with at least one anti-cancer therapy.
 35. The pharmaceutical composition for use according to claim 33 or 34, wherein the composition comprises 1.5 mg tivozanib and is to be administered to the subject for 21 days followed by 7 days without administration, wherein administration of the pharmaceutical composition for 21 days followed by 7 days without administration constitutes a treatment cycle.
 36. A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory cancer, wherein the subject has previously been treated with at least one anti-cancer therapy, the composition comprises 1.5 mg tivozanib and is to be administered to the subject for 21 days followed by 7 days without administration, and administration of the pharmaceutical composition for 21 days followed by 7 days without administration constitutes a treatment cycle.
 37. A pharmaceutical composition comprising tivozanib for use in treating a subject suffering from refractory renal cell carcinoma, wherein the subject has previously been treated with at least one anti-cancer therapy, the composition comprises 1.5 mg tivozanib and is to be administered to the subject for 21 days followed by 7 days without administration, and administration of the pharmaceutical composition for 21 days followed by 7 days without administration constitutes a treatment cycle.
 38. The pharmaceutical composition for use according to any one of claims 33-37, wherein: (a) the subject has previously been treated with at least one checkpoint inhibitor; (b) the subject has previously been treated with at least one vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI); (c) the subject has previously been treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) and a checkpoint inhibitor; or (d) the subject has previously been treated with two vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKI).
 39. The pharmaceutical composition for use according to any one of claims 33-38, wherein the subject is identified as having an International Metastatic-RCC Database Consortium (IMDC) risk score of favorable or intermediate prior to treating the subject.
 40. The pharmaceutical composition for use according to claim 39, wherein the IMDC risk category is favorable.
 41. The pharmaceutical composition for use according to claim 39, wherein the IMDC risk category is intermediate.
 42. The pharmaceutical composition for use according to any one of claim 33, 35, 36, or 38-41, wherein the refractory cancer is refractory renal cell carcinoma (RCC).
 43. The pharmaceutical composition for use according to any one of claims 33-42, wherein the tivozanib is tivozanib hydrochloride monohydrate.
 44. The pharmaceutical composition for use according to any one of claims 33-43, wherein the subject undergoes one or more treatment cycles with tivozanib.
 45. The pharmaceutical composition for use according to any one of claims 33-44, wherein the subject was previously treated with at least a first line anti-cancer therapy and a second line anti-cancer therapy.
 46. The pharmaceutical composition for use according to claim 45, wherein the first line and second line anti-cancer therapies were both vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR TKI) therapies.
 47. The pharmaceutical composition for use according to claim 45, wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a checkpoint inhibitor.
 48. The pharmaceutical composition for use according to claim 45, wherein the first line and second line anti-cancer therapies were selected from a VEGFR TKI and a systemic anti-cancer agent.
 49. The pharmaceutical composition for use according to claim 45, wherein the first line and second line anti-cancer therapies were selected from a checkpoint inhibitor and a systemic anti-cancer agent.
 50. The pharmaceutical composition for use according to any one of claim 38 or 46-49, wherein the VEGFR TKI is sunitinib, sorafenib, pazopanib, crizotinib, vandetinib, axitinib, cabozantinib, regorafenib, axinitib, or nintedanib.
 51. The pharmaceutical composition for use according to any one of claim 38, 47, or 49, wherein the checkpoint inhibitor is an anti-PDL1 or anti-PD1 inhibitor.
 52. The pharmaceutical composition for use according to claim 51, wherein the checkpoint inhibitor is nivolumab, pembrolizumab, cemiplimab, spartalizumab, camrelizumab, sintilimab, tislelizumab, toripalimab, prolgolimab cetrelimab, pidilizumab, BMS-936559, MDX-1105, atezolizumab, durvalumab, or avelumab.
 53. The pharmaceutical composition for use according to claim 48 or 49, wherein the systemic anti-cancer-agent is everolimus or temsirolimus.
 54. The pharmaceutical composition for use according to any one of claims 33-53, wherein the subject exhibits a complete or partial response to tivozanib after one treatment cycle, after two treatment cycles, after three treatment cycles, after four treatment cycles or after five treatment cycles.
 55. The pharmaceutical composition for use according to any one of claims 33-54, wherein the subject undergoes one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more than twelve treatment cycles.
 56. The pharmaceutical composition for use according to any one of claims 33-55, wherein the dose of tivozanib is reduced when a subject experiences a ≥Grade 3 drug-related adverse event.
 57. The pharmaceutical composition for use of any one of claims 33-55, wherein the dose of tivozanib is reduced for a subject experiencing moderate hepatic impairment (Child-Pugh class B).
 58. The pharmaceutical composition for use according to any one of claims 33-55, wherein the dose of tivozanib is reduced for a subject experiencing severe hepatic impairment (Child-Pugh class C).
 59. The pharmaceutical composition for use according to any one of claim 56-58, wherein the dose is reduced to 1.0 mg daily.
 60. The pharmaceutical composition for use according to any one of claims 56-58, wherein the dose is reduced to 1.5 mg every other day.
 61. The pharmaceutical composition for use according to any one of claims 56-58, wherein the dose is reduced to 1.0 mg every other day. 